Tryptophan, an essential amino acid, can be metabolized to several kinds of physiologically active metabolites. Accumulating data indicate that an altered metabolism of tryptophan and its active metabolites have important roles for the pathogenesis and development of complications of diabetes mellitus. Changes in tryptophan–kynurenine and tryptophan–methoxyindole pathways are related to several pathophysiological mechanisms of type 1 or type 2 diabetes. Particularly, serotonin, melatonin, and their receptors would be novel targets not only to better understand the pathogenesis of diabetes but also to develop new antidiabetic agents.